ArticleInternational journal of biological sciences2025
An efficient neural network of cooperating serotonergic and noradrenergic neurons in modulating sudden unexpected death in epilepsy.
Article in International journal of biological sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Sudden unexpected death in epilepsy (SUDEP) is a critical concern, with seizure-induced respiratory arrest (S-IRA) being a major contributing factor. The serotonergic (5-HT) and noradrenergic (NE) neurons have emerged as key modulators of SUDEP, yet the network-level interactions and specific mechanisms underlying their protective roles remain poorly defined. This study is the first to demonstrate a synergistic effect of 5-HT and NE in mitigating S-IRA and SUDEP using DBA/1 mice. Through a combination of pharmacological interventions, calcium signal recordings, and optogenetics, results show that elevating 5-HT and NE levels via 5-hydroxytryptophan and the norepinephrine reuptake inhibitor atomoxetine significantly reduced SUDEP incidence, with evidence of a robust synergistic interaction. Furthermore, venlafaxine, a selective serotonin-norepinephrine reuptake inhibitor, enhances the cooperative regulation of 5-HT and NE, further supporting their combined protective role. Crucially, the dorsal raphe-locus coeruleus-pre-Bötzinger complex (DR-LC-PBC) neural network is demonstrated as a critical pathway underlying this modulation. Targeted administration of the 5-HT2A/NE α-1 receptor antagonist and agonist into the PBC reveal their pivotal roles in mediating the protective effects of 5-HT and NE. Our study reveals that serotonergic and noradrenergic systems synergistically regulate SUDEP, and further identifies that the DR-LC-PBC neural circuit exerts a protective effect through activation of 5-HT2A and NE-α1 receptors within the PBC.
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